Etkovitz Nir, Tirosh Yitshak, Chazan Reut, Jaldety Yael, Daniel Limor, Rubinstein Sara, Breitbart Haim
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Dev Biol. 2009 Oct 15;334(2):447-57. doi: 10.1016/j.ydbio.2009.08.002. Epub 2009 Aug 8.
We have previously demonstrated the presence of active epidermal growth factor receptor (EGFR) and its involvement in sperm capacitation and the acrosome reaction; however, the mechanism of EGFR activation was not clear. We show here that the sperm EGFR can be transactivated by angiotensin II or by lysophosphatydic acid, two ligands which activate specific G-protein-coupled receptors (GPCR), or by directly activating protein kinase A using 8Br-cAMP. This transactivation occurs in noncapacitated sperm and is mediated by PKA, SRC and a metalloproteinase. We also show that the EGFR is activated in sperm incubated under in vitro capacitation conditions, without any added ligand, but not in bicarbonate-deficient medium or when PKA is blocked. Despite the fact that EGFR is activated in capacitated sperm, this state is not sufficient to induce the acrosome reaction. We conclude that the EGFR is stimulated during capacitation via PKA activation, while further activation of the EGFR in capacitated sperm is required in order to induce the acrosome reaction. The acrosome reaction can be induced by GPCR via the transactivation of the EGFR by a signaling pathway involving PKA, SRC and metalloproteinase and the EGFR down-stream effectors PI3K, PLC and PKC.
我们之前已经证明了活性表皮生长因子受体（EGFR）的存在及其在精子获能和顶体反应中的作用；然而，EGFR激活的机制尚不清楚。我们在此表明，精子EGFR可被血管紧张素II或溶血磷脂酸（两种激活特定G蛋白偶联受体（GPCR）的配体）反式激活，或通过使用8Br - cAMP直接激活蛋白激酶A来实现反式激活。这种反式激活发生在未获能的精子中，且由PKA、SRC和一种金属蛋白酶介导。我们还表明，在体外获能条件下孵育的精子中，EGFR会被激活，无需添加任何配体，但在缺乏碳酸氢盐的培养基中或PKA被阻断时则不会被激活。尽管EGFR在获能精子中被激活，但这种状态不足以诱导顶体反应。我们得出结论，在获能过程中EGFR通过PKA激活而被刺激，而在获能精子中EGFR的进一步激活是诱导顶体反应所必需的。顶体反应可由GPCR通过涉及PKA、SRC和金属蛋白酶以及EGFR下游效应器PI3K、PLC和PKC的信号通路对EGFR的反式激活来诱导。
